Adverse drug-drug interactions stemming from the induction or inhibition of cytochrome P-450 enzymes and/or the multidrug efftux pump, P-glycoprotein, are well recognized. With the widespread use of herbal dietary supplements, the potential for herb-drug interactions is emerging as a significant medical concern. Recent surveys indicate that 45 million Americans use herbal remedies regularly and that nearly 1 in 5 individuals taking prescription medications are also taking herbal supplements. This translates into more than 15 million adults taking prescription medications concurrently with herbal supplements. Furthermore, it has been noted that 70% of patients do not reveal their herb use to primary care providers. The risk of potential herb-drug interactions, therefore, is considerable. Documented herb-drug interactions are being reported in the medical literature. While a few in vivo studies indicate that the phytochemical components of botanical medicines can modulate hepatic drug metabolizing enzymes (cytochrome P-450s, CYP), and the multidrug efflux pump, P-glycoprotein (P-gp), no prospective in vivo studies assessing herb-drug interactions or their underlying mechanisms have been conducted in humans. The hypothesis to be tested is that concomitant use of herbal dietary supplements and conventional medications can elicit herb-drug interactions secondary to herb-mediated changes in drug absorption and elimination. The current proposal will evaluate changes in apparent oral clearance of phenotypic probe drugs as a means of assessing the effect of prolonged herbal supplementation on hepatic and intestinal CYP and/or P-gp activity in humans. The goals of this project are: (1) to assess which, if any, of 10 top-selling herbs in the United States pose a risk for CYP-mediated and/or P-gp-mediated herb-drug interactions; (2) to determine if prolonged berba| supplement use modulates specific CYP activities (i.e. CYPIA2, CYP2D6 and CYP3A4); and (3) whether prolonged herb use can modulate P-gp-mediated drug absorption and elimination.